Targeted, Evidence-Based Colorectal Cancer Therapies: Shifting the Patient Outcome

BaCkgrOund: Every 3.5 minutes, someone is diagnosed with colorectal cancer (CrC); every 9 minutes, someone dies from CrC; and every 5 seconds, someone who should be screened for CrC is not. The 5-year mortality for people diagnosed with CrC is approximately 40%; however, survival improves substantially if the cancer is diagnosed while still localized. OBjECTIvE: To track and review the rapid progress researchers have made in CrC. SuMMary: among patients who have CrC, approximately 50% will eventually develop liver metastases. The oncology field’s significant advances in the last few years, especially in CrC, challenge clinicians and patients. Multiple facets of care intersect in CrC: medical management, pharmacy management, symptom management, case management, and patient advocacy. CrC develops over many years as environmental and genetic factors interact. The american Cancer Society recommends screening all men and women older than 50 years and those at high risk at an earlier age. In the past, patients presenting with the same stage of CrC wereco nsidered similar. The staging criteria of the american joint Committee on Cancer recognizes that subsets of patients with varying survival statistics can be identified and that each patient requires a strategic approach. The u.S. Food and drug administration approval of irinotecan in 1996 and oxaliplatin in 2002 changed the landscape, and ultimately, the oral agent capecitabine and the biologics bevacizumab and cetuximab also significantly expanded treatment options. COnCLuSIOn: Clinicians must consider all available treatment options and regimen sequences across multiple lines of therapy, creating an early plan for each patient to extend survival while minimizing side effects.

3. Describe all drugsb yg eneric name unless theu se of theb rand name is necessaryt or educet he opportunity forconfusion amongreaders. 4. Strive to report subjectsofcurrent interest to managed care pharmacistsand other managedcareprofessionals.
This briefs ummary of what is needed to understandC RC can seem overwhelming to thegeneral practitioner andmanaged care decision makers whofacesimilar knowledgeneeds in other, andu ntil now, more common,h ealth fields.F ortunately,t he authorswhose workappears in this supplement have theexpertise necessaryt odescribe thei ssuesa nd thea bility to translate hard sciencei ntor eadable, accurate,t imelya rticles. Thosew ho complete this supplement will findthattheyare better prepared to address thec hangingh ealth care landscape that surrounds CRCtreatment.
OBjECTIvE: To track and review therapid progress researchers have made in CrC.
COnCLuSIOn: Clinicians must considerall availabletreatmentoptions and regimensequences acrossmultiplelines of therapy, creating an earlyplan foreach patient to extend survival whileminimizingsideeffects.
Numerous studiesh ave examined surgical ratesi np atients with metastaticc olon cancerw ho have hads urgicalr esection, andt he 5-year survival rate (the pointa tw hich oncologists consider ap atient cured) ranges from 25%t on early6 0%, compared with patients with metastaticd isease whoh aven ot hadr esection; their5 -years urvivorship rate is between5 % and1 0%. 27-33 Before combination chemotherapy and new treatment strategies were available, researchers identified several adverse prognostic factors that might preclude surgical resection. Prognosis is poorer when • the patients' original tumor is stage III or higher; • patients have multiple lesions; • the lesions are larger than 3 cm, involve satellite lesions, or occur in both lobes of the liver; • metastases occur within the first 12 to 30 months; and/or • metastases occur outside the liver and primary colon site.
Prognostic factors, however, may be evolving with the introduction of modern chemotherapy approaches. 5

■■ Approaches for Liver Metastases
Hepatic artery infusion (HAI) is the infusion of chemotherapy into the hepatic artery via a surgically implanted pump. Chemotherapy drugs can be injected periodically into the chamber of the pump, which then employs a gas-driven bellows to send chemotherapy by a hepatic artery catheter directly into the liver. Fluorodeoxyuridine (FUDR) has been the chemotherapy of choice for many years for HAI; compared with other agents, FUDR has the highest rate of extraction by the liver. Trials have compared HAI to systemic therapy with fluorouracil. 34-40 They have certain limitations and do not confirm a definitive survivorship benefit, but prior to the introduction of intravenous combination therapy, HAI produced the highest response rate seen in colon cancer: 50% to 60%. Since response rates with FOLFOX and FOLFIRI are similar to HAI, there may be a more limited role for HAI-delivered therapy.
Hepatic artery infusion has been tested for patients whose liver metastases have been resected. [34][35][36][37][38][39][40] These trials are also imperfect; however, they show without question that HAI recipients tend to experience less hepatic recurrence than those who did not.

Case 1: Patient Presentation
A 62-year-old nurse presented 10 months ago with a sigmoid colon lesion. She had a moderately differentiated, ulcerated 3 × 2 cm lesion (Stage II). After successful surgical resection, she received 6 months of adjuvant fluorouracil and leucovorin. Last month her carcinoembryonic antigen (CEA, used as a tumor marker for CRC) was elevated to 6.8 ng/mL. After seeing this individual, how would you proceed? Would you do a colonoscopy, a computed tomography (CAT) scan of the chest and abdomen and pelvis, a positron emission tomography (PET) scan, or an anti-CEA nuclear medicine scan?
A CAT scan is appropriate. This patient's rise in CEA in less than a year suggests the development of metastatic disease. Current surveillance strategies after surgery and adjuvant therapy for CRC are imperfect. Testing for CEA is the most widely used test, and it can be an early warning of metastases. Once it rises, the patient needs a full evaluation for metastatic disease. Colonoscopy is appropriate. In most individuals, the National Comprehensive Cancer Network (NCCN) 26 recommends colonoscopy 1 year after surgery to identify new polyps or a second primary tumor.
Although a PET scan would not be the first tool to evaluate metastatic disease, it can be helpful, particularly if further surgery to resect metastatic disease is being considered. The anti-CEA scan is available but is not widely used in the United States and certainly would not be a first choice.
The patient's colonoscopy was normal, but a CAT scan revealed 2 lesions (3 × 3 cm) in the right lobe of the liver. The PET scan confirmed the 2 lesions and found no other evidence of metastatic disease. The clinical team and patient chose surgical resection following chemother apy. The only opportunity to cure the person is with surgery, although the benefit of postoperative chemotherapy in this setting is unknown.

Sidebar 1
A regimen similar to FOLFOX (see below) that substitutes oral capecitabine for intravenous fluorouracil Experience with radiofrequency ablation (RFA,t he use of electrodest oh eata nd destroya bnormalt issue) in patients with hepaticm etastasis from CRCi si ncreasing. Open surgery, percutaneous RFA, andl aparoscopicR FA have been studied. Findings cannotconfirm that RFAiscurative-recurrencerates rangefromverylow to almost 50%depending on theunderlying presentation andnumberoflesions. 41-48 If cure is thegoal, surgicalresectionremains theg oldstandard, butinpatientswho are notg ood surgical candidates, RFAmay be an option.C urrently, many surgical patients have ac ombination of surgical resection with concurrent interoperative RFAf or lesionst hatc annotb e resected;the cure rate is unknown.
An updated report including4a dditionalp hase 3t rials( for at otal of 11 studies, N=5,768) validated theinitial analysis. 51 It confirmed thatt he percentage of patients with advanced CRC receiving 3d rugs during thec ourse of theird isease were likely to have longer OS.Again,the researchers gathe reddataonexposure to fluorouracil/leucovorin,irinotecan,and oxaliplatin.They concludedthatastrategyofmakingall active agents available to patients with advanced CRCappears to be more importantthan theu se of an individual therapy, andt hatc ombination therapy should remain thestandardofcarefor first-line treatment.

■■ TheBurden of ColorectalCancer
Medicare's need to address CRCi sl argely basedo nt he volume of patients affected;C RC is thes econd leadingc ause of cancer deathinthe United States.Because this diseasegenerallyaffects people aged 50 years or older andt he mean agea td iagnosis is 72 years,m ost affected Americansare Medicare-eligible. 1 As the "babyb oomers"a ge,the number of andb urdenassociatedwith Medicare-insured CRCp atientsw ill continue to rise.H ence, Medicare hasbeendiligently working to establishaway to man-ageCRC appropriately,not only clinicallybut also financially, so that allb eneficiaries have appropriate access to thei mproving standard of care.Medicareprovidescoveragefor more than 50% of all cancerpatients, andmanyprivate payers follow,orborrow significantly from,M edicare'sp oliciesf or coverage of andp ayment forcancercare.
As part of theN CD development process,a nd fort he first time regardingdrugtherapy,CMS formally instituted andbegan providingcoverage forproductsused in off-labelsituat ions while it evaluatedclinicalevidence; beneficiaries were grantedcoverage only if they were involved in clinicalt rialss anctionedb yC MS. By doingso, clinical evidence wassystematicallyand consistently collected andusedtodevelop theNCD over time.
This process is aC ED plan. 7 CMSh ad appliedC ED plans previously;inall cases, theprocess made headline news. Thefirst examined lung volume reductionsurgery in patients with severe emphysema.T he agency sought evidence to identify patients whow ould trulybenefit from thesesurgeries.Othersa ddressed theu se of positron emissiont omography scansf or Alzheimer's disease; bariatrics urgery forp atientso lder than6 5y ears;a nd expandingc overageo fi mplantablec ardioverterd efibrillators. When Medicare usesthe CEDprocess to make coverage decisions, it is ab urdeni na nd of itself. Some concerns includet he costs of thep rocess,t he provisiono ft rial medication data collection activitiesa nd analyses,a nd potentiale thical repercussionso f requiringparticipation in this clinicalevidencecollectionprocess forcoverage. Theseissueshave and will continue to be discussed in public forums.
ForC RC,t he CEDa nd NCDp rocesses allowed foral arge number of therapeuticoptions,and themilieu hasbeenchanging very quicklya sm oreo ptions continue to becomea vailable. In January2 005, aftera lmost 2y ears,C MS produced itsN CD foro ff-label useso fCRC therapies. TheN CD process is lengthy and, as in many diseases,t he optionsf or treatingC RC are changing so quicklythattaking2years forthese review processes mayb et oo slow.C MS and policy makers will continue to evaluate theneedand utility of thesep rocesses,balancing them with theresources required.
Currently, as exceptions to Medicarel aw,M edicareP artB covers select oral antineoplastics, because they arec onsidered prodrugs.F or example, thefluorouracilp recursorc apecitabine is oneo ft hese Medicare Part B-coveredd rugs.O ther products frequentlyu sedi nt he cancerp opulationa re provideradministered (e.g., injectables, infusables) anda re Part Bcovered, both as antineoplasticsa nd supportive care products such as hemopoetic agents,a ntiemeticp roducts, ands ome antinausea agents.I ti si mportant to note that cancerp atients oftenh ave an armamentariumo fo ther medications usedi n theiro verall cancerm anagement plans, such as oral or selfadministered therapiesu sedf or pain management andm ental health.These agents play asignificantroleinthe care of cancer patients,a nd they aren ot coveredu nder Part B, butr ather Part D.
In a2 004e ditorial in the NewE nglandJ ournal of Medicine, DeborahS chrag, MD,s ummarizeds omeo ft he cost concerns specifically related to CRC. 11 Shetracedthe progress of chemotherapeutica gentsf romt he 1960s,w henf luorouracilw as the primaryc hemotherapeutica gent available to treatC RC,t ot he 1990s,w hent he FDAb egan to approve what wast hen5n ew agents (irinotecan,o xaliplatin,c apecitabine, bevacizumab, and cetuximab) fort hisi ndication. These therapiesi mproveds ur-vivalfromameanof8monthswithout treatmentto12months with flourouracil.A fter 2002,m edians urvivali ncreased to 21 months with use of theneweragents, andlengthier survivals areexpected as data from ongoingtrialsiscollected.Doublingthe median survival increasedthe cost of therapy340 times, based on AW P-as taggeringf igure. Note thatt hisf igured oesn ot accountf or theincreased cost of simply living longer andbeing able to receive more cycles of therapy; it is basedo nan8-week treatmentplan. Thecost of managing metastases andsubsequent tumors is also notc onsidered in this editorialc omment. This is av eryr eal examp le of howc ostso fcaref or CRCare increasing at ratesthatare significantand especially meaningful forpatients as they ares haring thef inancial burden of receiving this care and, at times, with benefitsthatare beingpubliclydebated.

■■ Update
Thef ollowing is information regardingd evelopmentss ince the October symposiumrelevanttothe previous discussion.
Despitet he magnitudeo ft he increase in sheerc ost,t he actualb udgeti mpacti nm anaged care has continuedt ob e relatively small.The priceoftreatment is only 1factorthatmanaged care must weigh. That pricec an be exceptionallyh ighf or individuals, butt he population size is remarkably low, creating ap er-member-per-month( PMPM)i mpactt hati ss ometimes almost negligible-unliket reatmentst hath ave moderate costs buta re usedu biquitously,s ucha sstatins, antidepressants,a nd proton pump inhibitors.T reatment duration hast endedt ob e reasonably short. Usingt hese agents also offsetso ther costs, by eliminatingthe need forsurgery or decreasing hospitalizationor length of stay,a nd theiri ncremental benefitsa re elusive. Thus, cancertherapies have escapedmanaged care's aggressivenotice.
This meanst hatm anaged care pharmacy departmentsm ust become involvedi ns omed ecisions regardingo ncologyc are. This is an ew phenomenon.P harmacyh as notb eenc oncerned with traditionalc hemotherapyb ecause it wasp rimarily given parenterally andc overed by Medicare Part Ba so pposed to Medicare Part D. Instead, chemotherapy hastraditionally been a concernf or physicians' officesand hospitals. Thea dvento fo ral agents is changing ther eimbursement structure, andm anaged care pharmacy will need to integraten ew agents with theo lder medications andcreatecomprehensivecoverage. Thedifficultyis thatthisisaveryemotional subject because of thelife-threatening nature of CRC, andthe advocatesfor increasedavailability of new treatmentsr egardless of cost or evidence form as trongl obby. Advocateswill scrutinize effortstomanagecancerdrugs,and the amount of feedback andc omment tendst ob ed isproportionate compared with thenumberofpatientsactuallyaffected.

■■ Creating Context
Managedcareisbeginningt oestablish abenchmark describing thequality-of-life-per-year cost in termsofcost-effectiveness.For example, an ew product, panitumumab, wasa pprovedf or the treatmento fm etastaticC RC in patients whoh ave progressed on standard chemotherapy.T hisd rug, like many others, was fast-tracked basedonthe resultsofatrial of only 463patients. 11 Survival wass imilar in both thet reatment andc ontrol groups, butthe mean time to progressionwas 36 days longer forpatients treatedwithp anitumumab. 12 Itsa ctualp ricing is approximately $2,000 perw eek. Pharmacy departmentso rresponsemanagers must nota pproachthe cost of therapiesf or cancerinavacuum, ands houldd evelop ac ontext within whichc ost is onee lement of al argerp icture.T hese costsa re high relative to some issues; $14,000 to extend life for2m onthsi sn ot excessivec ompared wiht he costso fah ospitals tay, am ajors urgery,h omec are, or things of that nature.A ppropriate benchmarks should be other typesofcaregiven to thesepatients, whichispartofthe overall cost of cancer. Managed care hasroomfor improvement in evaluatingt he cost of care in general, andc anceri np articular. Our approacht oe nd-of-life issues is awkward; we prefer to discuss quality-of-lifeissues.
Onek ey wayt oi mprove quality of life fort erminalc ancer patients is good pain management. 13 Benchmarks forp ain management should encouragec ancer patients to manage pain effectivelya th ome. Better antineoplasticsa re also needed;t hey should be less toxicthanpreviouslyusedagentsand offerlonger survival.Quality of life, however, will only be sustainedifpatients can access otherservicesd uringthattimespan. Otherwise, the months of additional survival areo fp oorq uality,r epresenting abad outcome forall involved. 14 Oncology disease management programs must reacho ut to patients andnot necessarilydeal with theoncology issuesdirectly, buta ddress thet angentiali ssuest hati mpactc are, especially depressiona nd pain management.P &T committeesm ustn ot contemplatethe issuesand make decisionsinavacuum; many of thesedecisions aresocietal issuesconcernedwithdetermining the valueofnew therapiesmonetarilyand otherwise. In this respect, American societydiffersfromother cultures.For example, in the United Kingdom, combinationt herapy is notf irst-linef or CRC; fluorouracili s. If progressiono ccurs, combinationt herapy is likelythe next step.Americanshave notcollectivelymadeasingle decision about howC RC will be managed; individual care providers make thed ecisions.S erious national debate is needed on issues like this,and Medicare'sefforts areafirst step in that direction.Amoreintricate frameworkormatrixwould help us evaluate thesekinds of productsinterms of thecostssocietyiswilling to bear.D evelopinga nd usingab etterf rameworkw ould remove insurancecompanies,employers,patients, pharmacies,and individual oncologists from thed ebateo fw hatp rioritiess houldb e andwhere ourefforts arebestplaced. Unless Americansunite and deal with thesei ssues, individualsw ill continue to have to sort throughatremendousnumberofproblemswithlittleguidance.